Local anesthetics such as lidocaine are useful in pain relief in numerous applications, but suffer from the drawback of undesired blockade of motor function. They are non-selective sodium channel blockers that fail to discriminate between sodium channel activity required for normal ongoing sensation and similar activity involved in nociceptor signaling. The cationic sodium channel blocker, QX-314, selectively blocks sodium channel activity in nociceptor neurons when administered in the presence of capsaicin, an agonist for the transient receptor potential cation channel, subfamily V, member 1 (TRPV1). TRPV1 is preferentially expressed peripherally in small-diameter primary afferent nociceptors and is up-regulated in chronic pain states. However, TRPV1 is not present in the large diameter afferent neurons that convey tactile sensations nor is TRPV1 present in motor neuron efferent fibers.
QX-314 is the N-ethylated analog of lidocaine and bears a permanent positive charge. It is unable to cross the neuronal cell membrane when applied externally and has no effect on neuronal sodium-channel activity unless afforded access to the cell cytoplasm through open TRPV1 channels in which case it causes prolonged block of sodium-channel activity. Voltage-clamp single cell electrophysiology experiments illustrated that QX-314 permeates through capsaicin-activated TRPV1 channels and blocks sodium channel activity. In vivo, perisciatic administration of a QX-314/capsaicin combination produced pronounced and long-lasting nociceptor-selective nerve blockade.
The in vitro apparent affinity (IC50) of QX-314 for blocking sodium current in DRG neurons (when co-applied with 1 μM capsaicin and measured using the whole-cell voltage clamp approach) is modest at 30 μM.
There remains a need in the art for compounds which are useful in the management of long-term or chronic pain and compounds for pain management which minimize impairment of motor function.